ZA200200440B - Thienopyrimidines as phosphodiesterase inhibitors. - Google Patents
Thienopyrimidines as phosphodiesterase inhibitors. Download PDFInfo
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- ZA200200440B ZA200200440B ZA200200440A ZA200200440A ZA200200440B ZA 200200440 B ZA200200440 B ZA 200200440B ZA 200200440 A ZA200200440 A ZA 200200440A ZA 200200440 A ZA200200440 A ZA 200200440A ZA 200200440 B ZA200200440 B ZA 200200440B
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- South Africa
- Prior art keywords
- formula
- compounds
- compound
- physiologically acceptable
- acid
- Prior art date
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- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title 1
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- -1 COOA Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
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- 125000004185 ester group Chemical group 0.000 claims description 3
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- RTAIQZZASOBMQE-UHFFFAOYSA-N 4-[4-[(3-chloro-4-hydroxyphenyl)methylamino]-[1]benzothiolo[2,3-d]pyrimidin-2-yl]cyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1C1=NC(NCC=2C=C(Cl)C(O)=CC=2)=C2C3=CC=CC=C3SC2=N1 RTAIQZZASOBMQE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
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- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
a
Pa . @ 2002/0660 - Thienopyrimidines
The invention relates to compounds of the formula I —\ _R!
CH Xx ) 2
HN \ ¢ ) | R2 = N
NS Me :
ST NT TX in which
RY, R? in each case independently of one another are
H, A, OH, OA or Hal,
X is R*, R® or R®, which is monosubstituted by R’,
Rr* is linear or branched alkylene having 1-10 C atoms, in which one or two CH, groups can be replaced by -CH=CH- groups,
R’ is cycloalkyl or cycloalkyl alkylene having 5-12 C atoms,
R® is phenyl or phenylmethyl,
R’ is COOH, COOA, CONH,, CONHA, CON(A), or CN,
A is alkyl having 1 to 6 C atoms and
Hal is F, Cl, Br or I, where at least one of the radicals R! or R? is OH, and their physiologically acceptable salts.
re 2002705560
N 2
Wo Pyrimidine derivatives have been disclosed, for example, in EP 201 188 or WO 93/06104.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability.
In particular, they exhibit a specific inhibition of cGMP phosphodiesterase (PDE V).
Quinazolines having cGMP phosphodiesterase- inhibiting activity are described, for example, in J.
Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).
The biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104. The affinity of the compounds according to the invention for cGMP and . 20 cAMP phosphodiesterase is determined by the ascertainment of their ICsy values (concentration of the inhibitor which is needed in order to achieve a 50% inhibition of the enzyme activity).
For carrying out the determinations, enzymes isolated according to known methods can be used (e.g. W.J.
Thompson et al., Biochem. 1971, 10, 311). For carrying out the experiments, a modified “batch” method of
W.J. Thompson and M.M. Appleman (Biochem. 1979, 18, 5228) can be used.
The compounds are therefore suitable for the treatment of disorders of the cardiovascular system, in particular cardiac insufficiency, and for the treatment and/or therapy of potency disorders (erectile dysfunction). .
The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.
The compounds are effective as inhibitors of the phenylephrine-induced contractions in corpus
» . @® 3
N cavernosum preparations of hares. This biological action can be demonstrated, for example, according to the method which is described by F. Holmquist et al. in
J. Urol., 150, 1310-1315 (1993).
The inhibition of the contraction shows the efficacy of the compounds according to the invention for the therapy and/or treatment of potency disorders.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. In addition, they can be employed as intermediates for the preparation of further pharmaceutical active compounds.
The invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) a compound cf the formula II
L
Use
NN BS
ST NT TX in which
X has the meaning indicated, and L is Cl, Br, OH, SCH; or a reactive esterified OH group, is reacted with a compound of the formula III :
. » ® ¢
N R1 on 1
HN
R2 in which
R! and R? have the meanings indicated, or ~ b) in a compound of the formula I, a radical X is converted into another radical X by hydrolysing an ester group to a COOH group or converting a COOH group into an amide or into a cyano group or c) in a compound of the formula I, a radical R! and/or
R® is converted into another radical R!' and/or R? by converting an alkoxy group into a hydroxyl group, and/or a compound of the formula I is converted into one of its salts.
Above and below, the radicals R!, R?, R3, Rr? R®,
R®, R’, X and L have the meanings indicated in the formulae I, II and III, if not expressly stated otherwise.
A is alkyl having 1-6 C atoms.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 C atoms and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
Xx is an R?', R® or R® radical which is monosubstituted by R'.
R* is a linear or branched alkylene radical having 1-10 C atoms, where the alkylene radical is preferably, for example, methylene, ethylene,
~ 3 ) c “ ~ propylene, isopropylene, butylene, isobutylene, sec- butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, l-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2- ethylbutylene, l-ethyl-l-methylpropylene, l-ethyl-2- methylpropylene, 1,1,2- or 1,2,2-trimethylpropyvlene, linear or branched heptylene, octylene, nonylene or decylene.
RY is furthermore, for example, but-2-enylene or hex-3- enylene.
Ethylene, propylene or butylene is very particularly : preferred.
R® is cycloalkylalkylene having 5-12 C atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexyl- propylene or cyclohexylbutylene.
R®> is also cycloalkyl preferably having 5-7 C atoms.
Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
Hal is preferably F, Cl or Br, but also I.
The radicals R' and R?® can be identical or different and are preferably in the 3- or 4-position of the phenyl ring. They are, for example, in each case independently of one another H, alkyl, alkoxy, hydroxyl, F, Cl, Br or I. Preferably, they are independently of one another Hal and hydroxyl. At least one of the radicals R! and R?® is hydroxyl.
The radical R’ is preferably, for example,
COOH, COOCHj3, COOC;Hs, CONH,;, CON(CHj3),, CONHCH3; or CN.
It applies to the whole invention that all radicals which occur a number of times can be identical or different, i.e. are independent of one another.
Accordingly, the invention relates, in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
Some preferred groups of compounds can be expressed by the following subformulae Ia to Id, which
Te 6
W h correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which in Ia X is RY, phenyl or phenylmethyl, which is i substituted by COOH, COOA, CONH,, CONA3z,
CONHA or CN: in Ib R',R* in each case independently of one another are H, A, OH, OA or Hal,
X is RY, phenyl or phenylmethyl, which is substituted by COOH, COOA, CONH,, CONAz,
CONHA or CN; where at least one of the radicals R! and R®? is
OH; in Ic R',R® in each case independently of one another are H, A, OA or Hal,
X is alkylene having 2-5 C atoms, cyclohexyl, phenyl or phenylmethyl, which is monosubstituted by R’,
Rr’ is COOH or COOA,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I, where at least one of the radicals R' and R? is
OH; in Id RR! is Hal,
Rr? is OH,
X is alkylene having 2-5 C atoms, cyclohexyl, phenyl or phenylmethyl, which is monosubstituted by R’,
R’ is COOH or COOA,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I, : and their physiologically acceptable salts.
The compounds of the formula I and also the starting substances for their preparation are otherwise oo ® ;
NW > prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as
Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
In the compounds of the formula II or III, R!,
RR’, R) RY X and n have the meanings indicated, in particular the preferred meanings indicated.
If L is a reactive esterified OH group, this is preferably alkylsulfonyloxy having 1-6 Cc atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, in addition also 2-naphthalenesulfonyloxy).
The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
If desired, the starting substances can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
On the other hand, it is possible to carry out the reaction stepwise.
As a rule, the starting compounds of the ~ formulae II and III are known. If they are not known, ’ they can be prepared by methods known per se.
Compounds of the formula II can be obtained, e.g. by reaction with POCls, from the corresponding hydroxypyrimidines, which are synthesized from thiophene derivatives and CN-substituted alkylene carboxylic acid esters. (Eur. J. Med. Chem. 23, 453 (1988)).
The hydroxypyrimidines are prepared either by dehydrogenation of corresponding tetrahydrobenzo- : thienopyrimidine compounds or by the cyclization of 2- aminobenzothiophene-3-carboxylic acid derivatives with oo" ® . “ h aldehydes or nitriles, which is customary for the prepartion of pyrimidine derivatives (e.g. Houben Weyl
E9b/2).
Specifically, the reaction of the compounds of the formula II with the compounds of the formula III is carried out in the presence or the absence of an inert solvent at temperatures between approximately -20 and approximately 150°, preferably between 20 and 100°.
The addition of an acid-binding agent, for example of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine components can be favourable.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbontetra- chloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propancl, n- butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethyl- formamide (DMF) ; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned. \
It is furthermore possible to convert a radical
X in a compound of the formula I into another radical
X, e.g. by hydrolysing an ester or a cyano group to a
COOH group.
© @ 5
N Ester groups can be hydrolysed, for example, using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100°.
Carboxylic acids can be converted, for example using thionyl chloride, into the corresponding carboxylic acid chlorides and these can be converted into carboxamides. By elimination of water in a known manner, carbonitriles are obtained from these.
Compounds of the formula I in which R' and/or R? are OA can be converted according to known methods of ether cleavage into the corresponding compounds of the formula I in which R' and/or R? is hydroxyl.
An acid of the formula I can be converted into the associated acid addition salt using a base, for example by reaction of equivalent amounts of the acid and of the base in an inert solvent such as ethanol and subsequent evaporation. Suitable bases for this reaction are in particular those which yield physiologically acceptable salts.
Thus the acid of the formula I can be converted into the corresponding metal salt, in particular alkali metal or alkaline earth metal salt, or into the corresponding ammonium salt using a base (e.g. sodium or potassium hydroxide or carbonate).
For this reaction, suitable organic bases are in particular also those which yield physiologically acceptable salts, such as, for example, ethanolamine.
On the other hand, a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic,
T@ 10 “ N araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, : tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
The invention furthermore relates to the use of : the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non- chemical route. In this connection, they can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid vehicle or excipient and, if appropriate, in combination with one or more further active compounds.
The invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V inhibitors.
The invention further relates to pharmaceutical preparations, comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These preparations can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatine, carbohydrates such as lactose or starch, magnesium stearate, talc and
Ce 1 “ N petroleum jelly. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be employed in the control of diseases in which an increase in the cGMP (cyclic guanosin monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation. The compounds according to the invention can particularly be used in the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of potency disorders.
In this connection, the substances are as a rule preferably administered in doses of between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight.
The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, , body weight, general state of health, sex, on the diet, on the time and route of administration, and on. the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
yy A Above and below, all temperatures are indicated in °C. In the following examples, “customary working- up” means: if necessary, water is added, the pH is adjusted, if necessary, depending on the constitution of the final product, to a value of between 2 and 10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization)
M*
FAB (fast atom bombardment) (M+H)" :
Example 1
Methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin- 2-yl)propionate [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine] and 3-chloro-4- methoxybenzylamine (“A”) in N-methylpyrrolidone are stirred at 110° for 5 hours. The solvent is removed and the residue is worked up in the customary manner.
Methyl 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno- [{2,3-d]lpyrimidin-2-yl]propionate is obtained as a colourless oil.
The following is obtained analogously by reaction of “A” with methyl 2-(4-chlorobenzothieno[2,3-d]lpyrimidin-2- yl) acetate methyl 2-[4-(3-chloro-4-methoxybenzylamino)benzo- thieno[2,3-dlpyrimidin-2-yl]acetate.
The following is obtained analogously by reaction of “A”
oe " with methyl 4- (4-chlorobenzothieno[2,3-d]pyrimidin-2- yl)butyrate methyl 4-[{4-(3-chloro-4-methoxybenzylamino)benzo- thieno[2, 3-d]pyrimidin-2-yl]butyrate.
The following is obtained analogously by reaction of “A” with methyl 5-(4-chlorobenzothieno[2,3-d]lpyrimidin-2- yl)valerate methyl 5-[4-(3-chloro-4-methoxybenzylamino)benzo- thieno(2, 3-d]lpyrimidin~-2-yl]}valerate.
The following is obtained analogously by reaction of “A” with methyl 7-(4-chlorobenzothieno([2,3~-d]lpyrimidin-2- yl) heptanoate methyl 1-[4-(3-chloro-4-methoxybenzylamino)benzo- thieno[2,3-d]lpyrimidin-2-yl]heptanocate.
The following is obtained analogously by reaction of “A” with methyl 2-[4-(4-chlorobenzothieno(2,3-d]pyrimidin- 2-yl)cyclohex-l-yl]acetate methyl 2-{4-[4-(3-chloro-4-methoxybenzylamino) - benzothieno[2,3-d]pyrimidin-2-yl]cyclohex~1-yl}acetate
The following is obtained analogously by reaction of “A” with methyl 4-(4-chlorobenzothieno(2,3-d]lpyrimidin-2- yl) cyclohexanecarboxylate | } methyl 4-[4- (3-chloro-4-methoxybenzylamino)benzo- thieno[2, 3-d]lpyrimidin-2-yl]cyclohexanecarboxylate.
I 14 o ! Example 2
Methyl 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]propionate is dissolved in ethylene glycol monomethyl ether and stirred at 110° for 5 hours after addition of 32% NaOH. After addition of 20% HCl, the mixture is extracted with dichloromethane. By addition of petroleum ether, 3-[4-(3-chloro-4-methoxybenzylamino) benzothieno[2, 3-d] - pyrimidin-2-yl]propionic acid, m.p. 218°, is obtained.
The precipitated crystals are dissolved in isopropanol and treated with ethanolamine. After crystallization, 3-[4-(3-chloro-4-methoxybenzylamino) ~ benzothieno (2, 3-d]pyrimidin-2-yl]propionic acid, ethanolamine salt, is obtained.
The compounds 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]butyric acid, m.p. 225°; ethanolamine salt m.p. 150°; 5-[4-(3-chloro-4~methoxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]valeric acid, m.p. 210°; ethanolamine salt m.p. 141° are obtained analogously. ’ The carboxylic acids below are obtained analogously from the esters listed under Example 1: 2-[4-(3-chloro-4-methoxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]lacetic acid, 7-{4-(3-chloro-4-methoxybenzylamino)benzothieno- [2,3-d]lpyrimidin-2-~yllheptanoic acid, , 2-{4-{4-(3-chloro-4-methoxybenzylamino)benzo- thieno{2,3-d]pyrimidin-2-yl]cyclohex-1-yl}acetic acid,
w : ® 15 « A 4-[4~(3-chloro-4-methoxybenzylamino)benzothieno- [2,3~d]pyrimidin-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, m.p. 167°.
Example 3
A mixture of 1.5 a of methyl 4-(4- chlorobenzothieno[2, 3-d]pyrimidin-2- vl) phenylcarboxylate (“B”), prepared by dehydrogenation of the corresponding 5,6,7,8-tetrahydrobenzothieno(2,3- d]pyrimidine compound with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of :
N-methylpyrrolidone is heated at 110° for 4 hours.
After cooling, the mixture ‘is worked up in the customary manner. 2.6 g of methyl 4-[4-(3-chloro-4- methoxybenzylamino)benzothieno[2,3-dlpyrimidin-2-yl]- benzoate, m.p. 203-204°, are obtained.
Analogously to Example 2, 1.0 g of 4~-[4-(3-chloro-4-methoxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]benzoic acid, ethanolamine salt, : m.p. 189-190°, are obtained from 1.2 g of the ester thereof. :
The compound 4-[4~(3-chloro-4-methoxybenzyl- amino)benzothieno[2, 3-d]pyrimidin-2-yllphenylacetic acid, ethanolamine salt, m.p. 130°, is obtained analogously.
Example 4 1 equivalent of 3-[4-(3-chloro-4-methoxybenzyl- amino) benzothieno[2,3-d]pyrimidin-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2, 3-d]- pyrimidin-2-yl]propionyl chloride is obtained.
The mixture is transferred to aqueous ammonia, stirred for one hour and, after customary working up, 3-[4-(3-
© @ 16 o ® chloro-4-methoxybenzylamino)benzothieno([2,3-d]pyri- midin-2-yl]propionamide is obtained.
Example 5 1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino) - benzothieno[2, 3-d]pyrimidin-2~yl]propionamide is then added. The mixture is subsequently stirred for one hour. After customary working up, 3-[4-(3-chloro-4- methoxybenzylamino)benzothieno(2,3-dlpyrimidin-2-y1]- propionitrile is obtained.
Example 6
The compounds obtained in Examples 1 to 5 can be converted into the corresponding hydroxyl compounds by known methods of ether cleavage. The compounds below methyl 3-[4-(3-chloro-4-hydroxybenzylamino)benzo- thieno(2,3-dlpyrimidin-2-yl]lpropionate, methyl 2-[4-(3-chloro-4-hydroxybenzylamino)benzo- thieno[2,3-d]pyrimidin-2-yl]acetate, methyl 4-(4-(3-chloro-4-hydroxybenzylamino)benzo- thieno(2,3-d]lpyrimidin-2-yl]butyrate, methyl 5-[{4-(3-chloro-4-hydroxybenzylamino)benzo- thieno[2,3-d]lpyrimidin-2-yl]valerate, methyl 7-[4-(3-chloro-4-hydroxybenzylamino)benzo- thieno{2,3-d]pyrimidin-2-yl]heptanoate, } : methyl 2-{4-[4-(3-chloro-4-hydroxybenzylamino) - benzothieno[2, 3-d]pyrimidin-2-yl]lcyclohex-1l-yl}lacetate,
.® 2 methyl 4-[4-(3-chloro-4-hydroxybenzylamino)benzo- thieno([2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate, 3-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]propionic acid, 4-[{4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]butyric acid, 5-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]valeric acid, 2-[4-(3~-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]lacetic acid,
7-[4-(3-chloro-4-hydroxybenzylamino)benzothieno~ [2,3-d]pyrimidin-2-yl]heptanoic acid, 2-{4-[4~ (3-chloro-4-hydroxybenzylamino)benzo- thieno[2,3-d]pyrimidin-2-yl]cyclohex-1l-yl}acetic acid, 4-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, 4-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]lbenzoic acid, 4-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]phenylacetic acid, 30 . 3-[4~(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-~2-yl]propionamide, 3-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin~2-yl]propionitrile, are thus obtained.
\ o 18
RE Example 7
Analogously to Example 1, by reaction of 0.01 mol of methyl 4-(4-chlorobenzothieno[2, 3- dlpyrimidin-2-yl)cyclohexanecarboxylate with 0.02 mol of 3-chloro-4-hydroxybenzylamine in 40 ml of l-methyl- 2-pyrrolidone, after customary working up methyl 4-{4-(3-chloro-4-hydroxybenzylamino)benzo- thieno([2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate is obtained.
The compounds methyl 4-[4-(3-methoxy-4-hydroxybenzylamino)benzo- thieno (2, 3-d]pyrimidin-2-yl]cyclohexanecarboxylate and methyl 4-[4- (4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate are obtained analogously.
By ester hydrolysis analogously to Example 2, the compounds 4-[4- (3-chloro-4-hydroxybenzylamino)benzothieno- : (2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, m.p. 200-202°; 4-[4- (3-methoxy-4-hydroxybenzylamino)benzothieno~ [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, 4-[4- (4-hydroxybenzylamino)benzothieno[2,3-d]~ pyrimidin-2-yl]cyclohexanecarboxylic acid are obtained therefrom.
The compounds below
Claims (18)
1. Compounds of the formula I R! 2 _— HN R2 NP S N X in which R', R® in each case independently of one another are H, A, OH, OA or Hal, X is R*, R® or R® which is monosubstituted by R’, R* is linear or branched alkylene having 1-10 C. atoms, in which one or two CH; groups can be replaced by -CH=CH- groups, Rr’ is cycloalkyl or cycloalkyl alkylene having 5-12 C atoms, R® is phenyl or phenylmethyl, R’ is COOH, COOA, CONH,, CONHA, CON(A); or CN, A is alkyl having 1 to 6 C atoms and Hal is ¥, Cl, Br or I, where at least one of the radicals R! or R? is OH, and their physiologically acceptable salts.
2. Compounds of the formula I according to Claim 1
© @ 23 w (a) 3-[4-(3-chloro~-4-hydroxybenzylamino)benzo[4,5]~ thieno(2,3-dlpyrimidin-2-yl])propionic acid; (b) 7-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]- : thieno (2, 3-d]pyrimidin-2-yllheptanoic acid; (c) 5-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]- thieno([2,3-d]pyrimidin-2-yllvaleric acid; (d) 2-{4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]- thieno[2,3-d]lpyrimidin-2-yl]cyclohex-1-yllacetic acid; (e) 4-[4-(3-chloro-4-hydroxybenzylamino)benzothieno- [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid and their physiologically acceptable salts.
3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) a compound of the formula II L - ST NT TX in which X has the meaning indicated, Co and L is Cl, Br, OH, SCH; or a reactive esterified OH group, : is reacted with a compound of the formula III
\ ! pp. : R : CH ~~ 1} H,N R2 in which R' and R® have the meanings indicated, or _ : b) in a compound of the formula I, a radical X 1is converted into another radical X by hydrolysing an ester group to a COOH group or converting a COOH group into an amide or into a cyano group or c) in a compound of the formula I, a radical R' and/or R? is converted into another radical R!' and/or R® by converting an alkoxy group into a hydroxyl group, and/or a compound of the formula I is converted into one of its salts.
4. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable dose form together with at least one solid, liquid or semi-liquid vehicle or excipient.
5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts. : AMENDED SHEET y 25
6. A substance or composition for use in a method for the control of diseases of the cardiovascular system and for the treatment and/or therapy of potency disorders, said substance or composition comprising compounds of the formula I according to Claim 1 and their physiologically acceptable salts, and said method comprising administering said substance or composition.
7. Medicaments of the formula I according to Claim 1 and their physiologically acceptable salts as phosphodiesterase V inhibitors.
8. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament.
9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament for the treatment and/or therapy of potency disorders.
10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the manufacture of a medicament for the control of diseases of the cardiovascular system.
11. A substance or composition for use in a method for inhibiting phosphodiesterase V, said substance or composition comprising compounds of the formula I according to Claim 1 and their physiologically acceptable salts, and said method comprising administering said substance or composition.
12. A compound as claimed in Claim 1, substantially as herein described and illustrated. AMENDED SHEET
\. L 26
13. A process as claimed in Claim 3, substantially as herein described and illustrated.
14. A process as claimed in Claim 4, substantially as herein described and illustrated.
15. A pharmaceutical preparation as claimed in Claim 5, substantially as herein described and illustrated.
16. Use as claimed in Claim 8 or Claim 9 or Claim 10, substantially as herein described and illustrated.
17. A substance or composition for use in a method of treatment as claimed in Claim 6 or Claim 7 or Claim 11, substantially as herein described and illustrated.
18. A new compound, a new process for preparing a compound, a new process for producing a preparation, a new preparation, a new use of a compound as defined in Claim 1 or of a physiologically acceptable salt thereof, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
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DE19928146A DE19928146A1 (en) | 1999-06-19 | 1999-06-19 | New 3-benzylamino-benzothienopyrimidine derivatives inhibit phosphodiesterase V and are useful for treating cardiac insufficiency and impotence |
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EP (1) | EP1189907B1 (en) |
JP (1) | JP2003502429A (en) |
KR (1) | KR20020010719A (en) |
CN (1) | CN1144806C (en) |
AR (1) | AR024380A1 (en) |
AT (1) | ATE285412T1 (en) |
AU (1) | AU767273B2 (en) |
BR (1) | BR0011778A (en) |
CA (1) | CA2375278A1 (en) |
CZ (1) | CZ293901B6 (en) |
DE (2) | DE19928146A1 (en) |
ES (1) | ES2234613T3 (en) |
HK (1) | HK1047434B (en) |
HU (1) | HUP0201730A3 (en) |
MX (1) | MXPA01013228A (en) |
NO (1) | NO20016201L (en) |
PL (1) | PL351822A1 (en) |
PT (1) | PT1189907E (en) |
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SK (1) | SK18222001A3 (en) |
UA (1) | UA72256C2 (en) |
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DE19944604A1 (en) * | 1999-09-17 | 2001-03-22 | Merck Patent Gmbh | Amine derivatives |
DE10001021A1 (en) * | 2000-01-13 | 2001-07-19 | Merck Patent Gmbh | Pharmaceutical preparation |
DE10010612A1 (en) * | 2000-03-03 | 2001-09-27 | Merck Patent Gmbh | Treatment of erectile dysfunction without inducing circulatory side-effects, using penis-specific phosphodiesterase V inhibitors, preferably benzo (4,5) thieno (2,3-d) pyrimidine derivatives |
DE10017947A1 (en) * | 2000-04-11 | 2001-10-25 | Merck Patent Gmbh | Process for the preparation of benzo-fused heterocycles |
DE10031585A1 (en) * | 2000-06-29 | 2002-01-10 | Merck Patent Gmbh | 2-aminoalkyl-thieno [2,3-d] pyrimidine |
DE10107261B4 (en) * | 2001-02-16 | 2005-03-10 | Merck Patent Gmbh | Pharmaceutical composition |
WO2003035653A1 (en) * | 2001-10-26 | 2003-05-01 | Nippon Soda Co.,Ltd. | Pyridothienopyrimidine compound and salt thereof |
CA2620333A1 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
WO2007053596A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
JP2009536669A (en) | 2006-05-09 | 2009-10-15 | ブレインセルス,インコーポレイティド | Neurogenesis by angiotensin regulation |
EP2026813A2 (en) | 2006-05-09 | 2009-02-25 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
KR20090064418A (en) | 2006-09-08 | 2009-06-18 | 브레인셀즈 인코퍼레이션 | Combinations containing a 4-acylaminopyridine derivative |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
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DE19644228A1 (en) | 1996-10-24 | 1998-04-30 | Merck Patent Gmbh | Thienopyrimidines |
DE19819023A1 (en) | 1998-04-29 | 1999-11-04 | Merck Patent Gmbh | Thienopyrimidines |
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EP1189907B1 (en) | 2004-12-22 |
UA72256C2 (en) | 2005-02-15 |
MXPA01013228A (en) | 2002-07-02 |
AU5220400A (en) | 2001-01-09 |
NO20016201D0 (en) | 2001-12-18 |
CN1355805A (en) | 2002-06-26 |
ATE285412T1 (en) | 2005-01-15 |
PL351822A1 (en) | 2003-06-16 |
EP1189907A1 (en) | 2002-03-27 |
CN1144806C (en) | 2004-04-07 |
CA2375278A1 (en) | 2000-12-28 |
ES2234613T3 (en) | 2005-07-01 |
HK1047434A1 (en) | 2003-02-21 |
HUP0201730A2 (en) | 2002-09-28 |
DE50009042D1 (en) | 2005-01-27 |
RU2238274C2 (en) | 2004-10-20 |
DE19928146A1 (en) | 2000-12-21 |
AR024380A1 (en) | 2002-10-02 |
SK18222001A3 (en) | 2002-06-04 |
CZ293901B6 (en) | 2004-08-18 |
JP2003502429A (en) | 2003-01-21 |
WO2000078767A1 (en) | 2000-12-28 |
CZ20014422A3 (en) | 2002-03-13 |
HK1047434B (en) | 2005-01-28 |
HUP0201730A3 (en) | 2004-12-28 |
KR20020010719A (en) | 2002-02-04 |
AU767273B2 (en) | 2003-11-06 |
US6787548B1 (en) | 2004-09-07 |
BR0011778A (en) | 2002-04-23 |
PT1189907E (en) | 2005-05-31 |
NO20016201L (en) | 2001-12-18 |
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